Gene expression patterns can be used as prognostic biomarkers in various types of cancers. We aimed to identify a gene expression pattern for individual distant metastatic risk assessment in patients ...with locoregionally advanced nasopharyngeal carcinoma.
In this multicentre, retrospective, cohort analysis, we included 937 patients with locoregionally advanced nasopharyngeal carcinoma from three Chinese hospitals: the Sun Yat-sen University Cancer Center (Guangzhou, China), the Affiliated Hospital of Guilin Medical University (Guilin, China), and the First People's Hospital of Foshan (Foshan, China). Using microarray analysis, we profiled mRNA gene expression between 24 paired locoregionally advanced nasopharyngeal carcinoma tumours from patients at Sun Yat-sen University Cancer Center with or without distant metastasis after radical treatment. Differentially expressed genes were examined using digital expression profiling in a training cohort (Guangzhou training cohort; n=410) to build a gene classifier using a penalised regression model. We validated the prognostic accuracy of this gene classifier in an internal validation cohort (Guangzhou internal validation cohort, n=204) and two external independent cohorts (Guilin cohort, n=165; Foshan cohort, n=158). The primary endpoint was distant metastasis-free survival. Secondary endpoints were disease-free survival and overall survival.
We identified 137 differentially expressed genes between metastatic and non-metastatic locoregionally advanced nasopharyngeal carcinoma tissues. A distant metastasis gene signature for locoregionally advanced nasopharyngeal carcinoma (DMGN) that consisted of 13 genes was generated to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter distant metastasis-free survival (hazard ratio HR 4·93, 95% CI 2·99–8·16; p<0·0001), disease-free survival (HR 3·51, 2·43–5·07; p<0·0001), and overall survival (HR 3·22, 2·18–4·76; p<0·0001) than patients with low-risk scores. The prognostic accuracy of DMGN was validated in the internal and external cohorts. Furthermore, among patients with low-risk scores in the combined training and internal cohorts, concurrent chemotherapy improved distant metastasis-free survival compared with those patients who did not receive concurrent chemotherapy (HR 0·40, 95% CI 0·19–0·83; p=0·011), whereas patients with high-risk scores did not benefit from concurrent chemotherapy (HR 1·03, 0·71–1·50; p=0·876). This was also validated in the two external cohorts combined. We developed a nomogram based on the DMGN and other variables that predicted an individual's risk of distant metastasis, which was strengthened by adding Epstein–Barr virus DNA status.
The DMGN is a reliable prognostic tool for distant metastasis in patients with locoregionally advanced nasopharyngeal carcinoma and might be able to predict which patients benefit from concurrent chemotherapy. It has the potential to guide treatment decisions for patients at different risk of distant metastasis.
The National Natural Science Foundation of China, the National Science & Technology Pillar Program during the Twelfth Five-year Plan Period, the Natural Science Foundation of Guang Dong Province, the National Key Research and Development Program of China, the Innovation Team Development Plan of the Ministry of Education, the Health & Medical Collaborative Innovation Project of Guangzhou City, China, and the Program of Introducing Talents of Discipline to Universities.
Exhaustion of cytotoxic effector natural killer (NK) and CD8
T cells have important functions in the establishment of persistent viral infections, but how exhaustion is induced during chronic ...hepatitis C virus (HCV) infection remains poorly defined. Here we show, using the humanized C/O
mice permissive for persistent HCV infection, that NK and CD8
T cells become sequentially exhausted shortly after their transient hepatic infiltration and activation in acute HCV infection. HCV infection upregulates Qa-1 expression in hepatocytes, which ligates NKG2A to induce NK cell exhaustion. Antibodies targeting NKG2A or Qa-1 prevents NK exhaustion and promotes NK-dependent HCV clearance. Moreover, reactivated NK cells provide sufficient IFN-γ that helps rejuvenate polyclonal HCV CD8
T cell response and clearance of HCV. Our data thus show that NKG2A serves as a critical checkpoint for HCV-induced NK exhaustion, and that NKG2A blockade sequentially boosts interdependent NK and CD8
T cell functions to prevent persistent HCV infection.
Abstract In this work, we investigate an alternative channel for the formation of fast-spinning black hole–neutron star (BHNS) binaries, in which super-Eddington accretion is expected to occur in ...accreting BHs during the stable mass transfer phase within BH-stripped helium (BH–He-rich) star binary systems. We evolve intensive MESA grids of close-orbit BH–He-rich star systems to systematically explore the projected aligned spins of BHs in BHNS binaries, as well as the impact of different accretion limits on the tidal disruption probability and electromagnetic (EM) signature of BHNS mergers. Most of the BHs in BHNS mergers cannot be effectively spun up through accretion if the accretion rate is limited to ≲ 10 M ̇ Edd , where M ̇ Edd is the standard Eddington accretion limit. In order to reach high spins (e.g., χ BH ≳ 0.5), the BHs are required to be born less massive (e.g., ≲3.0 M ⊙ ) in binary systems with initial periods of ≲0.2–0.3 days and accrete material at ∼ 100 M ̇ Edd . However, even under this high accretion limit, ≳6 M ⊙ BHs are typically challenging to significantly spin up and generate detectable associated EM signals. Our population simulations suggest that different accretion limits have a slight impact on the ratio of tidal disruption events. However, as the accretion limit increases, the EM counterparts from the cosmological BHNS population can become bright overall.
Efficacy evaluation through human trials is crucial for advancing a vaccine candidate to clinics. Next-generation sequencing (NGS) can be used to quantify B cell repertoire response and trace ...antibody lineages during vaccination. Here, we demonstrate this application with a case study of Hecolin®, the licensed vaccine for hepatitis E virus (HEV). Four subjects are administered the vaccine following a standard three-dose schedule. Vaccine-induced antibodies exhibit a high degree of clonal diversity, recognize five conformational antigenic sites of the genotype 1 HEV p239 antigen, and cross-react with other genotypes. Unbiased repertoire sequencing is performed for seven time points over six months of vaccination, with maturation pathways characterize for a set of vaccine-induced antibodies. In addition to dynamic repertoire profiles, NGS analysis reveals differential patterns of HEV-specific antibody lineages and highlights the necessity of the long vaccine boost. Together, our study presents a quantitative strategy for vaccine evaluation in small-scale human studies.
Foodborne illnesses, particularly those caused by Salmonella enterica with its extensive array of over 2600 serovars, present a significant public health challenge. Therefore, prompt and precise ...identification of S. enterica serovars is essential for clinical relevance, which facilitates the understanding of S. enterica transmission routes and the determination of outbreak sources. Classical serotyping methods via molecular subtyping and genomic markers currently suffer from various limitations, such as labour intensiveness, time consumption, etc. Therefore, there is a pressing need to develop new diagnostic techniques. Surface‐enhanced Raman spectroscopy (SERS) is a non‐invasive diagnostic technique that can generate Raman spectra, based on which rapid and accurate discrimination of bacterial pathogens could be achieved. To generate SERS spectra, a Raman spectrometer is needed to detect and collect signals, which are divided into two types: the expensive benchtop spectrometer and the inexpensive handheld spectrometer. In this study, we compared the performance of two Raman spectrometers to discriminate four closely associated S. enterica serovars, that is, S. enterica subsp. enterica serovar dublin, enteritidis, typhi and typhimurium. Six machine learning algorithms were applied to analyse these SERS spectra. The support vector machine (SVM) model showed the highest accuracy for both handheld (99.97%) and benchtop (99.38%) Raman spectrometers. This study demonstrated that handheld Raman spectrometers achieved similar prediction accuracy as benchtop spectrometers when combined with machine learning models, providing an effective solution for rapid, accurate and cost‐effective identification of closely associated S. enterica serovars.
Objective
To enhance the accuracy in predicting lymph node metastasis (LNM) preoperatively in patients with papillary thyroid microcarcinoma (PTMC), refining the “low‐risk” classification for ...tailored treatment strategies.
Methods
This study involves the development and validation of a predictive model using a cohort of 1004 patients with PTMC undergoing thyroidectomy along with central neck dissection. The data was divided into a training cohort (n = 702) and a validation cohort (n = 302). Multivariate logistic regression identified independent LNM predictors in PTMC, leading to the construction of a predictive nomogram model. The model's performance was assessed through ROC analysis, calibration curve analysis, and decision curve analysis.
Results
Identified LNM predictors in PTMC included age, tumor maximum diameter, nodule‐capsule distance, capsular contact length, bilateral suspicious lesions, absence of the lymphatic hilum, microcalcification, and sex. Especially, tumors larger than 7 mm, nodules closer to the capsule (less than 3 mm), and longer capsular contact lengths (more than 1 mm) showed higher LNM rates. The model exhibited AUCs of 0.733 and 0.771 in the training and validation cohorts respectively, alongside superior calibration and clinical utility.
Conclusion
This study proposes and substantiates a preoperative predictive model for LNM in patients with PTMC, honing the precision of “low‐risk” categorization. This model furnishes clinicians with an invaluable tool for individualized treatment approach, ensuring better management of patients who might be proposed observation or ablative options in the absence of such predictive information.
We report the discovery of room temperature in-plane ferroelectricity in van der Waals In
2
Se
3
with β′ phase.
Van der Waals (vdW) assembly of layered materials is a promising paradigm for creating ...electronic and optoelectronic devices with novel properties. Ferroelectricity in vdW layered materials could enable nonvolatile memory and low-power electronic and optoelectronic switches, but to date, few vdW ferroelectrics have been reported, and few in-plane vdW ferroelectrics are known. We report the discovery of in-plane ferroelectricity in a widely investigated vdW layered material, β′-In
2
Se
3
. The in-plane ferroelectricity is strongly tied to the formation of one-dimensional superstructures aligning along one of the threefold rotational symmetric directions of the hexagonal lattice in the
c
plane. Surprisingly, the superstructures and ferroelectricity are stable to 200°C in both bulk and thin exfoliated layers of In
2
Se
3
. Because of the in-plane nature of ferroelectricity, the domains exhibit a strong linear dichroism, enabling novel polarization-dependent optical properties.
Bone morphogenetic protein 9 (BMP‐9) is a member of the transforming growth factor (TGF)‐β/BMP superfamily, and we have demonstrated that it is one of the most potent BMPs to induce osteoblast ...differentiation of mesenchymal stem cells (MSCs). Here, we sought to investigate if canonical Wnt/β‐catenin signalling plays an important role in BMP‐9‐induced osteogenic differentiation of MSCs. Wnt3A and BMP‐9 enhanced each other’s ability to induce alkaline phosphatase (ALP) in MSCs and mouse embryonic fibroblasts (MEFs). Wnt antagonist FrzB was shown to inhibit BMP‐9‐induced ALP activity more effectively than Dkk1, whereas a secreted form of LPR‐5 or low‐density lipoprotein receptor‐related protein (LRP)‐6 exerted no inhibitory effect on BMP‐9‐induced ALP activity. β‐Catenin knockdown in MSCs and MEFs diminished BMP‐9‐induced ALP activity, and led to a decrease in BMP‐9‐induced osteocalcin reporter activity and BMP‐9‐induced expression of late osteogenic markers. Furthermore, β‐catenin knockdown or FrzB overexpression inhibited BMP‐9‐induced mineralization in vitro and ectopic bone formation in vivo, resulting in immature osteogenesis and the formation of chondrogenic matrix. Chromatin immunoprecipitation (ChIP) analysis indicated that BMP‐9 induced recruitment of both Runx2 and β‐catenin to the osteocalcin promoter. Thus, we have demonstrated that canonical Wnt signalling, possibly through interactions between β‐catenin and Runx2, plays an important role in BMP‐9‐induced osteogenic differentiation of MSCs.
With the increased incidence of wine fraud, a fast and reliable method for wine certification has become a necessary prerequisite for the vigorous development of the global wine industry. In this ...study, a classification strategy based on three-dimensional fluorescence spectroscopy combined with chemometrics was proposed for oak-barrel and stainless steel tanks with oak chips aged wines. Principal component analysis (PCA), partial least squares analysis (PLS-DA), and Fisher discriminant analysis (FDA) were used to distinguish and evaluate the data matrix of the three-dimensional fluorescence spectra of wines. The results showed that FDA was superior to PCA and PLS-DA in classifying oak-barrel and stainless steel tanks with oak chips aged wines. As a general conclusion, three-dimensional fluorescence spectroscopy can provide valuable fingerprint information for the identification of oak-barrel and stainless steel tanks with oak chips aged wines, while the study will provide some theoretical references and standards for the quality control and quality assessment of oak-barrel aged wines.
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